High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension

Shinohara, Tsutomu; Moonen, Jan-Renier; Chun, Yoon Hong; Lee-Yow, Yannick C.; Okamura, Kenichi; Szafron, Jason M.; Kaplan, Jordan; Cao, Aiqin; Wang, Lingli; Taylor, Shalina; Isobe, Sarasa; Dong, Melody; Yang, Weiguang; Guo, Katherine; Franco, Benjamin D; Pacharinsak, Cholawat; Pisani, Laura J.; Saitoh, Shinji; Mitani, Yoshihide; Marsden, Alison L.; Engreitz, Jesse M.; Körbelin, Jakob; Rabinovitch, Marlene

doi:10.1101/2024.02.02.578526

Cited by 2 publications

(3 citation statements)

References 51 publications

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“…Furthermore, DSS and high shear stress (HSS) both induce EndMT and are associated with certain heart conditions like PAH. To understand this better, endothelial cells from individuals with heart conditions such as PAH were studied, which showed BMPR2-mediated EndMT following HSS [ 137 ]. Another protein called ETS-related gene (ERG) was reduced in these endothelial cells under HSS, which seems to play a role in triggering EndMT [ 137 ].…”

Section: Endmt In Cardiovascular Diseasesmentioning

confidence: 99%

“…To understand this better, endothelial cells from individuals with heart conditions such as PAH were studied, which showed BMPR2-mediated EndMT following HSS [ 137 ]. Another protein called ETS-related gene (ERG) was reduced in these endothelial cells under HSS, which seems to play a role in triggering EndMT [ 137 ]. Restoring ERG levels reduced the harmful effects of HSS, suggesting a potential treatment approach for heart conditions related to blood flow abnormalities [ 137 ].…”

Section: Endmt In Cardiovascular Diseasesmentioning

confidence: 99%

“…Another protein called ETS-related gene (ERG) was reduced in these endothelial cells under HSS, which seems to play a role in triggering EndMT [ 137 ]. Restoring ERG levels reduced the harmful effects of HSS, suggesting a potential treatment approach for heart conditions related to blood flow abnormalities [ 137 ]. Given the significant role of EndMT in PH, targeting EndMT has emerged as a promising therapeutic approach.…”

Section: Endmt In Cardiovascular Diseasesmentioning

confidence: 99%

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Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology

Singh,

Bhatt,

Nguyen

et al. 2024

IJMS

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Under different pathophysiological conditions, endothelial cells lose endothelial phenotype and gain mesenchymal cell-like phenotype via a process known as endothelial-to-mesenchymal transition (EndMT). At the molecular level, endothelial cells lose the expression of endothelial cell-specific markers such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and gain the expression of mesenchymal cell markers such as α-smooth muscle actin, N-cadherin, vimentin, fibroblast specific protein-1, and collagens. EndMT is induced by numerous different pathways triggered and modulated by multiple different and often redundant mechanisms in a context-dependent manner depending on the pathophysiological status of the cell. EndMT plays an essential role in embryonic development, particularly in atrioventricular valve development; however, EndMT is also implicated in the pathogenesis of several genetically determined and acquired diseases, including malignant, cardiovascular, inflammatory, and fibrotic disorders. Among cardiovascular diseases, aberrant EndMT is reported in atherosclerosis, pulmonary hypertension, valvular disease, fibroelastosis, and cardiac fibrosis. Accordingly, understanding the mechanisms behind the cause and/or effect of EndMT to eventually target EndMT appears to be a promising strategy for treating aberrant EndMT-associated diseases. However, this approach is limited by a lack of precise functional and molecular pathways, causes and/or effects, and a lack of robust animal models and human data about EndMT in different diseases. Here, we review different mechanisms in EndMT and the role of EndMT in various cardiovascular diseases.

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Section: Endmt In Cardiovascular Diseasesmentioning

confidence: 99%

Section: Endmt In Cardiovascular Diseasesmentioning

confidence: 99%

Section: Endmt In Cardiovascular Diseasesmentioning

confidence: 99%

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Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology

Singh,

Bhatt,

Nguyen

et al. 2024

IJMS

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Exploring the Endothelin-1 pathway in chronic thromboembolic pulmonary hypertension microvasculopathy

Feriel,

Alessandra,

Deborah

et al. 2024

Sci Rep

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Targeted vasopeptide therapies have significantly advanced the management of pulmonary arterial hypertension (PAH). However, due to insufficient preclinical evidence regarding the involvement of the endothelin-1 (ET-1) pathway in chronic thromboembolic pulmonary hypertension (CTEPH) pathophysiology, the potential of ET-1 receptor antagonism in treating CTEPH remains uncertain. In this study, we investigated the role of the ET-1 pathway in CTEPH microvasculopathy using a multifaceted approach. Plasma ET-1 levels were measured in a cohort of 59 CTEPH patients and 41 healthy controls. Additionally, we evaluated the expression of key ET-1 pathway members in pulmonary explants from CTEPH, idiopathic PAH, and control patients. We used an in vitro system to test the hypothesis that the turbulent flow, observed near the vascular obstructions pathognomonic of CTEPH, enhances ET-1 expression. Our findings were further validated in vivo using a CTEPH piglet model that contains distinct regions representing pre- and post-thrombus lung territories. We found a twofold increase in circulating ET-1 levels in CTEPH patients compared to healthy subjects. Pulmonary explants from CTEPH patients exhibited pronounced overexpression of ET-1, endothelin receptor A (ET A ), and phosphorylated myosin light chain (p-MLC) in muscularized pulmonary microvessels, suggesting heightened vascular contraction. In vitro experiments showed that turbulent flow facilitates ET-1 secretion compared to laminar flow regions. Additionally, in the CTEPH piglet model, elevated plasma ET-1 levels were observed compared to controls. Immunofluorescence and confocal microscopy analyses confirmed increased ETA and p-MLC in remodeled arteries from both pulmonary territories. However, ET-1 protein elevation was exclusively observed in the obstructed territory. These findings collectively indicate impaired vascular tone in microvessels of CTEPH patients and the CTEPH piglet model. Furthermore, our data implicates the ET-1 pathway in microvasculopathy, with turbulent flow playing a pathological role. These insights underscore the potential utility of ET-1 receptor antagonists as a promising therapeutic approach for CTEPH treatment.

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High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension

Cited by 2 publications

References 51 publications

Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology

Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology

Exploring the Endothelin-1 pathway in chronic thromboembolic pulmonary hypertension microvasculopathy

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